12-102866662-C-T

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PM1PM2PM5PP3PP5_Very_Strong

The NM_000277.3(PAH):c.443G>A(p.Gly148Asp) variant causes a missense, splice region change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 13/23 in silico tools predict a damaging outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G148S) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 32)

Consequence

PAH
NM_000277.3 missense, splice_region

Scores

Splicing: ADA: 0.9896

Clinical Significance

Likely pathogenic reviewed by expert panel P:2

Conservation

PhyloP100: 5.24

Variant links:

Genes affected

PAH (HGNC:8582): (phenylalanine hydroxylase) This gene encodes a member of the biopterin-dependent aromatic amino acid hydroxylase protein family. The encoded phenylalanine hydroxylase enzyme hydroxylates phenylalanine to tyrosine and is the rate-limiting step in phenylalanine catabolism. Deficiency of this enzyme activity results in the autosomal recessive disorder phenylketonuria. [provided by RefSeq, Aug 2017]

PAH links:

LOC124902999 (HGNC:):

LOC124902999 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 15 ACMG points.

PM1

In a turn (size 3) in uniprot entity PH4H_HUMAN there are 5 pathogenic changes around while only 0 benign (100%) in NM_000277.3

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr12-102866663-C-T is described in Lovd as [Pathogenic].

PP3

Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.

PP5

Variant 12-102866662-C-T is Pathogenic according to our data. Variant chr12-102866662-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 872837.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr12-102866662-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PAH	NM_000277.3 link	c.443G>A	p.Gly148Asp	missense_variant, splice_region_variant	Exon 5 of 13	ENST00000553106.6	NP_000268.1	P00439A0A024RBG4
PAH	NM_001354304.2 link	c.443G>A	p.Gly148Asp	missense_variant, splice_region_variant	Exon 6 of 14		NP_001341233.1
PAH	XM_017019370.2 link	c.443G>A	p.Gly148Asp	missense_variant, splice_region_variant	Exon 5 of 7		XP_016874859.1
LOC124902999	XR_007063428.1 link	n.807+1435C>T		intron_variant	Intron 1 of 2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
PAH	ENST00000553106.6 link	c.443G>A	p.Gly148Asp	missense_variant, splice_region_variant	Exon 5 of 13	1	NM_000277.3	ENSP00000448059.1	P00439
PAH	ENST00000549111.5 link	n.539G>A		splice_region_variant, non_coding_transcript_exon_variant	Exon 5 of 6	1
PAH	ENST00000307000.7 link	c.428G>A	p.Gly143Asp	missense_variant, splice_region_variant	Exon 6 of 14	5		ENSP00000303500.2	J3KND8
PAH	ENST00000551988.5 link	n.530+10800G>A		intron_variant	Intron 4 of 4	3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Phenylketonuria

Pathogenic:2

May 26, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Not Available"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Not Available"). This variant has been observed in individual(s) with phenylketonuria (PMID: 15589814, 21147011). ClinVar contains an entry for this variant (Variation ID: 872837). This variant is not present in population databases (ExAC no frequency). This sequence change replaces glycine with aspartic acid at codon 148 of the PAH protein (p.Gly148Asp). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and aspartic acid. This variant disrupts the p.Gly148 amino acid residue in PAH. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 8535445, 7726156, 9012412, 10679941, Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

Jan 26, 2020

ClinGen PAH Variant Curation Expert Panel

Significance: Likely pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

The c.443G>A (p.Gly148Asp) variant in PAH has been reported in multiple individuals with PKU (BH4 deficiency excluded). (PMID: 21147011, 15589814). This variant is absent in population databases (PM2). This variant was detected with pathogenic variant IVS4nt5G>T (c.441+5G>T). Computational evidence supports a deleterious effect. In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PP4_Moderate, PM2, PM3_supporting, PP3. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.97

BayesDel_addAF

Pathogenic

0.55

BayesDel_noAF

Pathogenic

0.55

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

1.0

D;D

Eigen

Pathogenic

1.1

Eigen_PC

Pathogenic

0.97

FATHMM_MKL

Uncertain

0.96

LIST_S2

Pathogenic

0.98

D;D

M_CAP

Pathogenic

0.81

MetaRNN

Pathogenic

0.99

D;D

MetaSVM

Pathogenic

0.95

MutationAssessor

Pathogenic

4.4

H;.

PrimateAI

Pathogenic

0.89

PROVEAN

Pathogenic

-6.8

D;D

REVEL

Pathogenic

0.94

Sift

Uncertain

0.0020

D;D

Sift4G

Uncertain

0.0030

D;D

Polyphen

1.0

D;.

Vest4

0.95

MutPred

0.89

Gain of relative solvent accessibility (P = 0.0479);.;

MVP

0.99

MPC

0.26

ClinPred

1.0

GERP RS

6.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.90

gMVP

0.97

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

0.99

dbscSNV1_RF

Pathogenic

0.82

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over